The clinical use of platinum complexes in cancer chemotherapy is now well established. The clinical utility of cisplatin, cis-[PtCl.sub.2 (NH.sub.3).sub.2 ] or DDP, may be classified principally as curable (testicular cancer), sensitive (ovarian) and responsive (head and neck, small cell lung), and this spectrum of activity is matched by the "second-generation" analog carboplatin, [Pt(NH.sub.3).sub.2 (CBDCA)], where CBDCA=1,1'-cyclobutanedicarboxylate. The principal advantage of the latter complex is considered to be the reduction in the severe nephrotoxicity of the parent complex, the spectrum of activity being very similar, although this may eventually change.
The structure-activity relationships developed for platinum complexes has led to the development of a large number of complexes with antitumor activity. The basic adaptation of the parent molecule involved use of other amines besides NH.sub.3 and modification of the leaving group by substitution of the chloride with other groups such as carboxylate, dicarboxylate or sulfate.
The potential for use of sulfur-bound dimethylsulfoxide (DMSO) as the leaving group in complexes of type cis-[Pt(am).sub.2 (DMSO).sub.2 ].sup.2+ has been outlined by N. Farrell, "Platinum, Gold and Other Metal Chemotherapeutic Agents", ACS Symposium 209, 279 (1983) and N. Farrell, J. Chem. Soc. (Chem. Comm.) 1014 (1980). The rationale for these complexes is that despite the high trans influence of DMSO, which would be expected to labilize the group trans to it, the mutual labilization of the two DMSO ligands results in initial loss of DMSO to give aquo species, maintaining the cis-Pt(am).sub.2 moiety intact. Kinetic studies confirmed these observations; S. Lanza, D. Minnitti, R. Romeo, and M. L. Tobe, Inorg. Chem. 22, 2006 (1983). Further hydrolysis would give the active diaquo species: EQU [Pt(am).sub.2 (DMSO).sub.2 ].sup.2+ .fwdarw.[Pt(am).sub.2 (DMSO)(H.sub.2 O)].sup.2+ .fwdarw.[Pt(am).sub.2 (H.sub.2 O) .sub.2 ].sup.2+
This series of bis(DMSO) complexes were not, however, active in vivo, due perhaps to the 2+ charge and lack of penetration into the cell. A further problem may be the rate at which the second sulfoxide ligand reacts, either to give the active diaquo species or in a direct reaction with DNA, the purported intracellular target of Pt complexes; A. L. Pinto and S. J. Lippard: Biochem. Biophys. Acta 780, 167 (1985). The series [Pt(am).sub.2 (DMSO)Cl].sup.+ has been studied for their kinetic parameters and it is stated that this series is not antitumor active; A. R. Khokhar and M. L. Tobe, J. Clin. Hematol. Oncol. 7(1), 114 (1977).
Factors which limit more widespread clinical use of cisplatin are the development of drug resistance and dose-limiting toxicity such as nephrotoxicity. A number of bidentate amines, such as 1,2-diaminocyclohexane (dach) and 1,1'-bis(aminomethyl)cyclohexane (damch), give complexes which are non-cross-resistant with cisplatin. A limiting factor in development of dach and damch complexes has been both aqueous solubility and chemical stability. A recent approach to development of suitable, stable, water-soluble complexes, described in my copending application Ser. No. 180,956, filed Apr. 13, 1988, is the use of asymmetric sulfoxides in the general series of cationic complexes cis-[PtCl(am).sub.2 (R'R"SO)].sup.+X-, where (am).sub.2 represents two monodentate amines or a bidentate amine; R'R"SO is an asymmetric substituted sulfoxide and X.sup.- is a counter-anion, usually nitrate. Such cationic sulfoxide complexes violate the previously understood and accepted structure-activity relationships for antitumor activity both because of their charge and the presence of the sulfur atom directly bound to platinum. The structure-activity relationships originally delineated for cisplatin stated unequivocally that a condition for good antitumor activity was that the complex must be neutral of form [Pt(amine).sub.2 X.sub.2 ], where X is a leaving group such as chloride, carboxylate, sulfate, etc.